A sex-specific prediction model is not enough to achieve equality for women in preventative cardiovascular medicine.

This commentary refers to ‘SCORE2 risk prediction algorithms: new models to estimate 10-year risk of cardiovascular disease in Europe’, by the SCORE2 working group and European Society of Cardiology (ESC) Cardiovascular Risk Collaboration, https://doi.org/10.1093/eurheartj/ehab309 and the discussion piece ‘SCORE2 models allow consideration of sex-specific cardiovascular disease risks by region’, by S. Hageman et al., https://doi.org/10.1093/eurheartj/ehab761

Metformin and high-sensitivity cardiac troponin I and T trajectories in type 2 diabetes patients: a post-hoc analysis of a randomized controlled trial

Background: Metformin has favorable effects on cardiovascular outcomes in both newly onset and advanced type 2 diabetes, as previously reported findings from the UK Prospective Diabetes Study and the HOME trial have demonstrated. Patients with type 2 diabetes present with chronically elevated circulating cardiac troponin levels, an established predictor of cardiovascular endpoints and prognostic marker of subclinical myocardial injury. It is unknown whether metformin affects cardiac troponin levels. The study aimed to evaluate cardiac troponin I and T trajectories in patients with diabetes treated either with metformin or placebo. Methods: This study is a post-hoc analysis of a randomized controlled trial (HOME trial) that included 390 patients with advanced type 2 diabetes randomized to 850 mg metformin or placebo up to three times daily concomitant to continued insulin treatment. Cardiac troponin I and T concentrations were measured at baseline and after 4, 17, 30, 43 and 52 months. We evaluated cardiac troponin trajectories by linear mixed-effects modeling, correcting for age, sex, smoking status and history of cardiovascular disease. Results: This study enrolled 390 subjects, of which 196 received metformin and 194 received placebo. In the treatment and placebo groups, mean age was 64 and 59 years; with 50% and 58% of subjects of the female sex, respectively. Despite the previously reported reduction of macrovascular disease risk in this cohort by metformin, linear mixed-effects regression modelling did not reveal evidence for an effect on cardiac troponin I and cardiac troponin T levels [− 8.4% (− 18.6, 3.2), p = 0.150, and − 4.6% (− 12, 3.2), p = 0.242, respectively]. A statistically significant time-treatment interaction was found for troponin T [− 1.6% (− 2.9, − 0.2), p = 0.021] but not troponin I concentrations [− 1.5% (− 4.2, 1.2), p = 0.263]. Conclusions: In this post-hoc analysis of a 4.3-year randomized controlled trial, metformin did not exert a clinically relevant effect on cardiac troponin I and cardiac troponin T levels when compared to placebo. Cardioprotective effects of the drug observed in clinical studies are not reflected by a reduction in these biomarkers of subclinical myocardial injury. Trial registration ClinicalTrials.gov identifier NCT00375388

Sex Differences in Cardiac Troponin Trajectories Over the Life Course

BACKGROUND: Cardiac troponin concentrations are lower in women than men. We examined whether age- and risk factor-related changes in cardiac troponin over the life course differ by sex and if the trajectory of cardiac troponin was informative in respect of cardiovascular outcomes in women and men in the general population. METHODS: In the Whitehall II cohort, high-sensitivity cardiac troponin I concentrations were measured on 3 occasions over a 15-year period. Using linear mixed-effects models, the sex-specific trajectories of cardiac troponin were evaluated, and the relationship with conventional cardiovascular risk factors determined. Using multistate joint models, the association between sex-specific trajectories of cardiac troponin and a composite outcome of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death was evaluated. RESULTS: In 2142 women and 5151 men (mean, 58±7 and 57±7 years of age, respectively), there were 177 (8.3%) and 520 (10.1%) outcome events, respectively, during a median follow-up of 20.9 (25th to 75th percentile, 15.8–21.3) years. Cardiac troponin concentrations were persistently lower in women than in men (median baseline concentration: 2.4 [25th to 75th percentile, 1.7–3.6] ng/L versus 3.7 [25th to 75th percentile, 2.6–5.8] ng/L, respectively, P<0.001), with women exhibiting a relatively larger increase with advancing age as compared with men (Pinteraction<0.001). Apart from age, a significant and divergent interaction with sex was found for the association between cardiac troponin and body mass index (BMI) (Pinteraction=0.008) and diabetes (Pinteraction=0.003). During follow-up, cardiac troponin concentrations were associated to the outcome in both women and men (adjusted hazard ratio per 2-fold difference [95% CI, 1.34 (1.17–1.52) and 1.30 (1.21–1.40), respectively], Pinteraction=0.752). The slope of cardiac troponin was significantly associated with the outcome in women, but not in men (adjusted hazard ratio [95% CI, 2.70 (1.01–7.33) and 1.31 (0.62–2.75), respectively], Pinteraction=0.250). CONCLUSIONS: Trajectories of cardiac troponin differ between women and men in the general population, with differing associations to conventional risk factors and cardiovascular outcomes. Our findings highlight the importance of a sex-specific approach when serial cardiac troponin testing is applied for cardiovascular risk prediction

Multiple cardiac biomarkers to improve prediction of cardiovascular events:Findings from the Generation Scotland Scottish Family Health Study

Background: Many studies have investigated whether single cardiac biomarkers improve cardiovascular risk prediction for primary prevention but whether a combined approach could further improve risk prediction is unclear. We aimed to test a sex-specific combined cardiac biomarker approach for cardiovascular risk prediction. Methods: In the Generation Scotland Scottish Family Health Study, N-terminal pro-B-type natriuretic peptide (NT-proBNP), growth differentiation factor-15 (GDF-15), cardiac troponin I (cTnI), cardiac troponin T (cTnT), and C-reactive protein (CRP) were measured in stored serum using automated immunoassays. Sex-specific Cox models that included SCORE2 risk factors evaluated addition of single and combined biomarkers for prediction of major adverse cardiovascular events (MACE). Combined biomarker models were compared to a baseline model that included SCORE2 factors.Results: The study population comprised 18,383 individuals (58.9% women, median age of 48 years [25th-75th percentile, 35-58 years]). During the median follow up of 11.6 (25th-75th percentile, 10.8-13.0) years, MACE occurred in 942 (5.1%) individuals. The greatest increase in discrimination with addition of individual biomarkers to base model was for women GDF-15 and for men NT-proBNP (change in c-index: +0.010 for women and +0.005 for men). For women, combined biomarker models that included GDF-15 and NT-proBNP (+0.012) or GDF-15 and cTnI (+0.013), but not CRP or cTnT, further improved discrimination. For men, combined biomarker models that included NT-proBNP and GDF-15 (+0.007), NT-proBNP and cTnI (+0.006), or NT-proBNP and CRP (+0.008), but not cTnT, further improved discrimination. Conclusions: A combined biomarker approach, particularly the use of GDF-15, NT-proBNP and cTnI, further refined cardiovascular risk estimates.<br/

Influence of age on the diagnosis of myocardial infarction

The 99th centile of cardiac troponin, derived from a healthy reference population, is recommended as the diagnostic threshold for myocardial infarction, but troponin concentrations are strongly influenced by age. Our aim was to assess the diagnostic performance of cardiac troponin in older patients presenting with suspected myocardial infarction. METHODS: In a secondary analysis of a multicenter trial of consecutive patients with suspected myocardial infarction, we assessed the diagnostic accuracy of high-sensitivity cardiac troponin I at presentation for the diagnosis of type 1, type 2, or type 4b myocardial infarction across 3 age groups (<50, 50–74, and ≥75 years) using guideline-recommended sex-specific and age-adjusted 99th centile thresholds. RESULTS: In 46 435 consecutive patients aged 18 to 108 years (mean, 61±17 years), 5216 (11%) had a diagnosis of myocardial infarction. In patients <50 (n=12 379), 50 to 74 (n=22 380), and ≥75 (n=11 676) years, the sensitivity of the guideline-recommended threshold was similar at 79.2% (95% CI, 75.5–82.9), 80.6% (95% CI, 79.2–82.1), and 81.6% (95% CI, 79.8–83.2), respectively. The specificity decreased with advancing age from 98.3% (95% CI, 98.1–98.5) to 95.5% (95% CI, 95.2–95.8), and 82.6% (95% CI, 81.9–83.4). The use of age-adjusted 99th centile thresholds improved the specificity (91.3% [90.8%–91.9%] versus 82.6% [95% CI, 81.9%–83.4%]) and positive predictive value (59.3% [57.0%–61.5%] versus 51.5% [49.9%–53.3%]) for myocardial infarction in patients ≥75 years but failed to prevent the decrease in either parameter with increasing age and resulted in a marked reduction in sensitivity compared with the use of the guideline-recommended threshold (55.9% [53.6%–57.9%] versus 81.6% [79.8%–83.3%]. CONCLUSIONS: Age alters the diagnostic performance of cardiac troponin, with reduced specificity and positive predictive value in older patients when applying the guideline-recommended or age-adjusted 99th centiles. Individualized diagnostic approaches rather than the adjustment of binary thresholds are needed in an aging population

Vitamin K Antagonists, Non-Vitamin K Antagonist Oral Anticoagulants, and Vascular Calcification in Patients with Atrial Fibrillation

Background  Vitamin K antagonists (VKAs) are associated with coronary artery calcification in low-risk populations, but their effect on calcification of large arteries remains uncertain. The effect of non-vitamin K antagonist oral anticoagulants (NOACs) on vascular calcification is unknown. We investigated the influence of use of VKA and NOAC on calcification of the aorta and aortic valve. Methods  In patients with atrial fibrillation without a history of major adverse cardiac or cerebrovascular events who underwent computed tomographic angiography, the presence of ascending aorta calcification (AsAC), descending aorta calcification (DAC), and aortic valve calcification (AVC) was determined. Confounders for VKA/NOAC treatment were identified and propensity score adjusted logistic regression explored the association between treatment and calcification (Agatston score > 0). AsAC, DAC, and AVC differences were assessed in propensity score-matched groups. Results  Of 236 patients (33% female, age: 58 ± 9 years), 71 (30%) used VKA (median duration: 122 weeks) and 79 (34%) used NOAC (median duration: 16 weeks). Propensity score-adjusted logistic regression revealed that use of VKA was significantly associated with AsAC (odds ratio [OR]: 2.31; 95% confidence interval [CI]: 1.16-4.59; p  = 0.017) and DAC (OR: 2.38; 95% CI: 1.22-4.67; p  = 0.012) and a trend in AVC (OR: 1.92; 95% CI: 0.98-3.80; p  = 0.059) compared with non-anticoagulation. This association was absent in NOAC versus non-anticoagulant (AsAC OR: 0.51; 95% CI: 0.21-1.21; p  = 0.127; DAC OR: 0.80; 95% CI: 0.36-1.76; p  = 0.577; AVC OR: 0.62; 95% CI: 0.27-1.40; p  = 0.248). A total of 178 patients were propensity score matched in three pairwise comparisons. Again, use of VKA was associated with DAC ( p  = 0.043) and a trend toward more AsAC ( p  = 0.059), while use of NOAC was not (AsAC p  = 0.264; DAC p  = 0.154; AVC p  = 0.280). Conclusion  This cross-sectional study shows that use of VKA seems to contribute to vascular calcification. The calcification effect was not observed in NOAC users

Implementation of a high sensitivity cardiac troponin i assay and risk of myocardial infarction or death at five years:Observational analysis of a stepped wedge, cluster randomised controlled trial

Abstract:Objective: To evaluate the impact of implementing a high sensitivity assay for cardiac troponin I on long term outcomes in patients with suspected acute coronary syndrome. Design: Secondary observational analysis of a stepped wedge, cluster randomised controlled trial. Setting: 10 secondary and tertiary care centres in Scotland, UK. Participants: 48 282 consecutive patients with suspected acute coronary syndrome. Myocardial injury was defined as any high sensitivity assay result for cardiac troponin I &gt;99th centile of 16 ng/L in women and 34 ng/L in men. Intervention: Hospital sites were randomly allocated to either early (n=5 hospitals) or late (n=5 hospitals) implementation of a high sensitivity cardiac troponin I assay with sex specific diagnostic thresholds. Main outcome measure: The main outcome was myocardial infarction or death at five years. Results: 10 360 patients had cardiac troponin concentrations greater than the 99th centile, of whom 1771 (17.1%) were reclassified by the high sensitivity assay. The five year incidence of subsequent myocardial infarction or death before and after implementation of the high sensitivity assay was 29.4% (5588/18 978) v 25.9% (7591/29 304), respectively, in all patients (adjusted hazard ratio 0.97, 95% confidence interval 0.93 to 1.01), and 63.0% (456/720) v 53.9% (567/1051), respectively, in those reclassified by the high sensitivity assay (0.82, 0.72 to 0.94). After implementation of the high sensitivity assay, a reduction in subsequent myocardial infarction or death was observed in patients with non-ischaemic myocardial injury (0.83, 0.75 to 0.91) but not in those with type 1 or type 2 myocardial infarction (0.92, 0.83 to 1.01 and 0.98, 0.84 to 1.14). Conclusions: Implementation of a high sensitivity cardiac troponin I assay in the assessment of patients with suspected acute coronary syndrome was associated with a reduced risk of subsequent myocardial infarction or death at five years in those reclassified by the high sensitivity assay. Improvements in outcome were greatest in patients with non-ischaemic myocardial injury, suggesting a broader benefit beyond the identification of myocardial infarction. Trial registration: ClinicalTrials.gov NCT01852123.</p